RESEARCH Open Access Diaphragm weakness in mechanically ...

RESEARCH Open Access

Diaphragm weakness in mechanically ventilatedcritically ill patientsGerald S Supinski*† and Leigh Ann Callahan†

Abstract

Introduction: Studies indicate that mechanically ventilated patients develop significant diaphragm muscleweakness, but the etiology of weakness and its clinical impact remain incompletely understood. We assesseddiaphragm strength in mechanically ventilated medical ICU patients, correlated the development of diaphragmweakness with multiple clinical parameters, and examined the relationship between the level of diaphragmweakness and patient outcomes.

Methods: Transdiaphragmatic twitch pressure (PdiTw) in response to bilateral magnetic stimulation of the phrenicnerves was measured. Diaphragm weakness was correlated with the presence of infection, blood urea nitrogen,albumin, and glucose levels. The relationship of diaphragm strength to patient outcomes, including mortality andthe duration of mechanical ventilation for successfully weaned patients, was also assessed.

Results: We found that infection is a major risk factor for diaphragm weakness in mechanically ventilated medicalICU patients. Outcomes for patients with severe diaphragm weakness (PdiTw <10 cmH2O) were poor, with amarkedly increased mortality (49%) compared to patients with PdiTw ≥10 cmH2O (7% mortality, P = 0.022). Inaddition, survivors with PdiTw <10 cmH2O required a significantly longer duration of mechanical ventilation (12.3 ±1.7 days) than those with PdiTw ≥10 cmH2O (5.5 ± 2.0 days, P = 0.016).

Conclusions: Infection is a major cause of severe diaphragm weakness in mechanically ventilated patients.Moreover, diaphragm weakness is an important determinant of poor outcomes in this patient population.

IntroductionThe number of mechanically ventilated patients in med-ical ICUs (MICUs) in the United States has increaseddramatically over the past 20 years. Currently 800,000patients per year require mechanical ventilation [1].Many of these patients die, with an annual mortalityexceeding 200,000 [2]. In addition, survivors oftenrequire prolonged, expensive hospital stays to achieveliberation from mechanical ventilation [3]. In the past itwas thought that the severity of lung disease was themajor determinant of outcomes in MICU patients, butrecent work indicates that mechanically ventilatedpatients develop significant diaphragm weakness [4-6].Diaphragm weakness is primarily thought to occur as a

consequence of ventilator-induced diaphragm inactivity,

with weakness progressing as duration of mechanicalventilation increases [7,8]. Theoretically, however, thereare other mechanisms by which diaphragm weaknesscan develop. Animal studies indicate that experimentalmodels of infection induce significant diaphragm weak-ness [9,10]. In addition, data suggest that azotemia,hyperglycemia, and low systemic albumin levels are riskfactors for prolonged mechanical ventilation and couldtheoretically be associated with the development ofrespiratory muscle weakness [11-13]. The importance ofinfection, azotemia, hyperglycemia, and reduced albuminlevels as risk factors for the development of diaphragmweakness in mechanically ventilated patients, however, isunknown.Diaphragm weakness is also commonly thought to pre-

dispose patients to sustained respiratory failure, greatlyprolonging the time required to wean patients frommechanical ventilation and worsening clinical outcomes.No previous study, however, has examined the quantita-tive relationship of diaphragm function, assessed using a

* Correspondence: [email protected]† Contributed equallyDepartment of Internal Medicine, Division of Pulmonary, Critical Care andSleep Medicine, University of Kentucky, 740 South Limestone Room L-543,Lexington, KY 40536-0284, USA

Supinski and Ann Callahan Critical Care 2013, 17:R120http://ccforum.com/content/17/3/R120

© 2013 Supinski and Callahan; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the CreativeCommons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, andreproduction in any medium, provided the original work is properly cited.

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purely objective, nonvolitional technique (such as bilat-eral anterior magnetic phrenic nerve stimulation), to clin-ical outcomes in mechanically ventilated patients.The purpose of the present study, therefore, was to

objectively measure diaphragm strength in a cross-section of mechanically ventilated MICU patients and totest the specific hypothesis that the severity of dia-phragm weakness would correlate with one or more ofthe following clinical factors: the presence of infection,blood urea nitrogen level, serum albumin level, and/orblood glucose level. We also ascertained the relationshipof diaphragm strength to patient outcomes, includingmortality, rate of transfer to long-term acute care(LTAC) facilities, and the subsequent duration ofmechanical ventilation in MICU survivors who weresuccessfully extubated. Finally, to determine whetherclinicians were cognizant of the severity of diaphragmweakness present in their patients, we asked the attend-ing MICU physicians to estimate diaphragm strengthand compared these estimates with objectively deter-mined measurements.

MethodsStudy protocolStudies were performed on adult ICU patients requiringmechanical ventilation in the University of KentuckyMICU for more than 24 hours. The protocol wasapproved by the University of Kentucky InstitutionalReview Board and informed consent was obtained fromsubjects and their surrogates. The following wererecorded: diaphragm strength by measuring the trans-diaphragmatic twitch pressure (PdiTw); respiratory staticsystem compliance and airway resistance using themechanical ventilator diagnostic module; basic clinicaldata; clinician estimates of diaphragm strength; and out-comes, including mortality, rate of transfer to LTACfacilities, and additional days required for continuedmechanical ventilation until successful extubation.

Exclusion criteriaIf the attending physician anticipated that the patientwould be successfully weaned from mechanical ventila-tion in less than 24 hours, or determined that thepatient was too unstable to tolerate the measurements,subjects were not screened for study inclusion. Exclu-sion criteria included: requirement for high dose press-ors (≥15 μg/minute norepinephrine or ≥15 mg/kg/minute dopamine); elevated positive end-expiratorypressure (PEEP ≥15 cmH2O); presence of a cardiacpacemaker or implanted defibrillator; administration ofneuromuscular blocking agents within 48 hours prior tostudy entry; recent variceal bleeding; pregnancy; incar-ceration; or institutionalization.

Determination of transdiaphragmatic twitch pressureDiaphragm strength was assessed by measuring PdiTwin response to bilateral anterior magnetic stimulation ofthe phrenic nerves. PdiTw is an objective, nonvolitionaltechnique that has been verified in previous studies toprovide the most accurate assessment of diaphragmstrength in humans [14-16]. Moreover, previous studiesdemonstrate that this technique can reliably and repro-ducibly measure diaphragm contractile strength inmechanically ventilated ICU patients [4-6].Subjects were studied in the supine position with the

head of the bed elevated at 30°. Two sterile commerciallyavailable balloon-tipped catheters (Ackrad Laboratories,NJ, USA) were passed through the nose after applicationof local anesthetic (1 milliliter of 1% Lidocaine gel); onecatheter was placed in the stomach, while the other wasplaced in the esophagus. Following initial placement, thecatheters were connected to Validyne pressure transdu-cers (Validyne Engineering, Northridge, CA, USA) toverify correct positioning. Correct placement of the gas-tric balloon was confirmed by demonstrating a positivepressure in response to pressure applied over the sto-mach; correct placement of the esophageal balloon wasverified by demonstrating that the pressure waveformhad an end-expiratory pressure similar to the total PEEPlevel and also mirrored airway pressure changes withinspiratory efforts during airway occlusion.After confirming accurate balloon placement, subjects

were left to breathe quietly for 10 minutes beforefurther assessment. Figure of eight magnetic coilsattached to dual Magstim 200 stimulators (Jali Medical,Inc., Waltham, MA, USA) were then placed bilaterallyover the phrenic nerves adjacent to the border of thesternocleidomastoid muscles. Magnetic field strengthwas adjusted to maximal levels (100%) and simultaneoussupramaximal magnetic pulses were delivered to thephrenic nerves bilaterally to elicit maximal twitch trans-diaphragmatic pressures (that is, PdiTw). Stimuli wereinterpolated between adjacent ventilator breaths and thetransdiaphragmatic pressures elicited by these stimuliwere recorded while simultaneously and transientlyoccluding the external circuit connecting the endotra-cheal tube to the ventilator with a pneumatic valve. Aminimum of five twitches were recorded, with at least30 seconds between adjacent stimuli. To verify stimuliwere supramaximal, additional twitches were performedat reduced magnetic field strengths (90 to 95%). PdiTwwas calculated as follows:

pdiTw = � gastric pressure − � esophageal pressure

The best three measurements in response to 100%levels of magnetic stimulation were averaged for eachsubject and recorded as the PdiTw.


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Measurement of respiratory system static compliance andairway resistanceFor these assessments, the ventilator was set to asquare-wave flow pattern with an inspiratory plateau.The ventilator rate was then transiently increased (forexample, 30 to 60 seconds) to suppress spontaneousrespirations. After reaching a steady state, the peak pres-sure and the plateau pressure were recorded and intrin-sic PEEP was determined using an end-expiratoryocclusion maneuver. Inspiratory airway resistance of therespiratory system was calculated as:

(Peak pressure - plateau pressure)/inspiratory flow

The effective static compliance of the respiratory sys-tem was calculated as:

Tidal volume/(plateau pressure − (total PEEP))

Once measurements were completed, the ventilatorwas returned to its previous mode and settings.

Clinical parametersData for the following clinical parameters were collectedas close as possible to the time of determination ofPdiTw levels: age, gender, clinical diagnoses, the pre-sence of positive cultures for infectious agents, antibioticregimen, glucose, albumin, blood urea nitrogen (BUN),Sequential Organ Failure Assessment scores, Charlsoncomorbidity indexes, vital signs, duration of mechanicalventilation prior to PdiTw measurement, mechanicalventilation mode, FiO2 (fraction of inspired oxygen),tidal volume and rate, percentage of patient triggeredbreaths, and most recent arterial blood gas values. Allrecorded values were obtained within 24 hours ofPdiTw assessment.

Clinician estimatesAttending physicians were asked to estimate the level ofdiaphragm strength using a form with qualitative descrip-tors of muscle weakness (see Additional file 1).

Statistical analysisWhenever data were normally distributed and varianceswere similar, parametric tests were used to comparegroups. When these conditions were not met, nonpara-metric tests were used to make comparisons. Data analyzedusing parametric tests are presented as mean ± standarderror of the mean. Data analyzed using nonparametric testsare presented as median ± confidence intervals. Linearregression was utilized to assess the relationship of BUN,albumin, glucose and duration of prior mechanical ventila-tion to PdiTw level. Analysis of variance was employed tocompare PdiTw across cohorts of patients with differentlevels of ventilator triggering. Fisher exact testing and

receiver operating curve analyses were used to determinethe boundary between weak and strong PdiTw groups thatbest discriminated between survival and mortality [17].

ResultsDiaphragm strength in medical ICU patientsSixty subjects were recruited into the study. PdiTw couldnot be measured in three subjects because the magneticcoils could not be effectively positioned due to anatomicconstraints (Subjects 18, 43, and 48). Detailed informa-tion for the 57 subjects in whom PdiTw measurementswere successfully performed is provided in Additionalfile 2. To verify that we achieved supramaximal levels ofmagnetic stimulation, we plotted the PdiTw valuesachieved using 95% magnetic field strength levels againstPdiTw values attained using 100% magnetic fieldstrength, as shown in Figure 1A. The PdiTw levelsobtained using 95% and 100% field strength levels werevirtually identical, arguing that supramaximal neural sti-mulation was achieved when employing 100% magneticfield strength for these studies. Moreover, the twitchdeterminations were highly reproducible in individualsubjects, with a coefficient of variation for the best threemeasurements performed at 100% stimulator outputaveraging 7% for the 57 subjects. High levels of PEEP canalter the relationship between the actual intrinsic dia-phragm strength and the measured PdiTw. In the presentcohort of patients, however, only one study subject hadPEEP >8 cmH2O. As a result, PEEP-induced hyperinfla-tion did not appreciably impact our data analysis (seeAdditional file 3).This cohort of 57 mechanically ventilated subjects had amean PdiTw of 7.9 ± 0.6 cmH2O. This value is similarto values reported previously in mechanically ventilatedcritically ill patients [4-6]. For comparison, normalhealthy adults average a PdiTw of 29.3 ± 2.8 cmH2O inour laboratory; this value is similar to that reported forhealthy adults in the literature [4,14]. Estimates of dia-phragm strength from the attending physicians wereobtained for 51 subjects. Clinicians did not accuratelypredict the level of diaphragm strength of their patients(Figure 1B). In many cases, patients with profound levelsof diaphragm weakness were thought to have normalstrength. Strength was overestimated in 46 of 51patients, was correctly estimated in five patients, andwas never underestimated.

Risk factors for the development of diaphragm weaknessData were analyzed to determine which factors correlatedwith the level of diaphragm weakness in mechanically ven-tilated subjects. We found a strong relationship betweenthe presence of infection and diaphragm weakness. In all,41 subjects were classified as being infected based on apositive test for a pathogenic organism from a sterile site


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(40 patients) or a clinical diagnosis of bacterial pneumonia(one patient; cultures were lost for this individual). All 41subjects classified as infected were thought by the attend-ing physicians who were providing care for these patientsto be infected clinically and all 41 of these patientsreceived antibiotic therapy (Tables 2 and 3). Theremaining 16 patients were classified as non-infected(see Table 2). Infected patients had a median PdiTw ofonly 5.5 cmH2O (25 to 75% confidence levels of 4.0 to7.9 cmH2O), while patients without clinical evidence ofinfection had a median PdiTw of 13.0 cmH2O (25to 75% confidence levels of 11.0 to 14.7, P < 0.001)(Figure 2A). Of interest, while infection was associatedwith greater diaphragm weakness, infected patients didnot have significantly different respiratory mechanicalparameters (that is, respiratory system static compli-ance and airway resistance) from non-infected patients(Figure 2B, C).

We also found that there was no significant correlationbetween PdiTw and either BUN, albumin, or glucose levels(Figures 3A, B, C). While many patients were receivingsteroids (regimens provided in Table 3), we found no cor-relation between steroid dosage and PdiTw values (seeAdditional file 4). In addition, we found no relationshipbetween the number of days subjects had been onmechanical ventilation prior to testing and the level ofPdiTw (Figure 4A). This finding contrasts with recentreports suggesting that patients on mechanical ventilationfor longer durations have progressively lower levels of dia-phragm strength [6,18]. One potential explanation for thisdifference is that the patients examined in the presentstudy were all ventilated with assist modes of mechanicalventilation, while previous work that demonstrated astrong relationship between mechanical ventilation andthe development of diaphragm weakness specificallyrestricted examination to patients who were on controlled

0 5 10 15 200

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>3026-3016-256-15

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(A) (B)

Figure 1 Transdiaphragmatic twitch pressure: measured levels and physician estimates. (A) Transdiaphragmatic twitch pressure (PdiTw)levels for the 57 subjects included in the analysis. Each symbol represents a single subject and plots the PdiTw level obtained in response tostimulation of the phrenic nerves with 95% of maximum magnetic field strength (y axis) against the PdiTw obtained in response to stimulationof the phrenic nerves with 100% of maximum magnetic field strength (x axis). All data cluster along the line of identity, indicating thatsupramaximal stimulation was achieved during 100% magnetic field stimulation. If supramaximal conditions had not been achieved, data pointswould have fallen to the right of the line of identity. (B) Measured PdiTw levels compared with levels predicted for each subject by theirattending physicians; each symbol represents data from a single patient. Red symbols below the line (46 out of 51 determinations) indicatedeterminations for which physicians overestimated diaphragm strength (that is, PdiTw).


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mechanical ventilation with little or no spontaneousrespiratory activity [18]. As shown in Figure 4B, ourpatient population had a high level of spontaneous respira-tory activity, with the majority of patients triggering morethan 75% of ventilator breaths. Of interest, we also foundthat PdiTw was similar over the range of levels of ventila-tor triggering observed in the present study (Figure 4C).

Relationship of diaphragm strength to patient outcomesTo assess the relationship between diaphragm strengthand mortality, we plotted PdiTw against patient days ofsurvival (Figure 5A). Patients that died were significantlyweaker than survivors, with PdiTw averaging 6.3 ± 0.6and 8.9 ± 0.9 cmH2O, respectively, for these two groups(P < 0.04). To further analyze this relationship, we usedFisher exact testing and ROC curve analyses to deter-mine the level of PdiTw that best discriminated betweensurvival and mortality [17]. Both forms of testing foundthis boundary to be 10 cmH2O. Patients with PdiTw≥10 cmH2O had only a 7% mortality (one death out of14 patients) while patients with PdiTw <10 cmH2O hada 49% mortality (17 deaths out of 35 patients, P = 0.022for comparison of the two groups; Figure 5B). Becauseindices of lung function may influence mortality, wealso compared respiratory system static compliance andairway resistance between patients with PdiTw ≥10cmH2O and patients with Pdi <10 cmH2O (Figures 5C, D).Lung mechanics were not significantly different betweenthese two groups of patients, indicating that level of dia-phragm function, not lung function, best correlated withsurvival in our patients. In addition, patients with PdiTw≥10 cmH2O and PdiTw <10 cmH2O had similar SequentialOrgan Failure Assessment scores (7.6 ± 0.6 and 6.9 ± 0.4,respectively) and Charlson Comorbidity Indices (2.7 ± 0.5and 2.5 ± 0.3, respectively).We also evaluated the possible mechanism(s) by which

diaphragm weakness may have influenced the incidenceof death. In this cohort, five of the patients with PdiTw

<10 cmH2O that died were receiving vasopressors whencare was withdrawn; vasopressors and mechanical venti-lation were stopped simultaneously in these patients anddeath occurred as a result of combined respiratory fail-ure and hypotension. In the remaining 12 patients withPdiTw <10 cmH2O that died, none met criteria forbrain death, all maintained motor drive to the respira-tory pump, none were on vasopressors, and the onlyform of continuous life support that these patients werereceiving was mechanical ventilation. Prior weaningtrials had been attempted and all 12 patients had failedto reach extubation criteria. Death occurred in these 12patients when mechanical ventilation was withdrawn.These data suggest that the presence of severe dia-phragm weakness limited weaning trial success in these12 patients and may have influenced the decision towithdraw care.With respect to other outcome measures, seven patients

with PdiTw <10 cmH2O were transferred to a long-termventilator facility while only one of the patients withPdiTw ≥10 cmH2O was transferred to a LTAC facility. Inaddition, the time required to wean survivors frommechanical ventilation was a function of PdiTw, with timeto wean increasing significantly for patients with PdiTw<10 cmH2O (Figure 6A). On average, duration of mechan-ical ventilation after PdiTw measurements was 12.3 ± 1.7days for patients with PdiTw <10 cmH2O but only 5.5 ±2.0 days for patients with PdiTw ≥10 cmH2O (P = 0.016).In contrast, duration of mechanical ventilation had norelationship to either respiratory system static compliance(Figure 6B) or airway resistance (Figure 6C).

DiscussionThe present study indicates that diaphragm weakness is asignificant determinant for poor outcomes in mechani-cally ventilated MICU patients We found that the inci-dence of death was 49% in the patients with the weakestdiaphragms (that is, with PdiTw <10 cmH2O) but wasonly 7% for patients with PdiTw levels ≥10 cmH2O. Onepossible explanation for the far greater mortality inpatients with PdiTw <10 cmH2O could be that weaknessis simply a marker for multiorgan system failure and thatdamage to these other organs was primarily responsiblefor patient deaths. Surprisingly, however, we found thatindices of disease severity (for example, lung mechanics,Sequential Organ Failure Assessment scores, CharlsonComorbidity Indexes) were almost identical in patientswith PdiTw levels ≥10 cmH2O and in patients withPdiTw <10 cmH2O, suggesting that the relationshipbetween diaphragm weakness and mortality is not simplyan epiphenomenon. Moreover, the majority of patientdeaths (12 of 18 deaths) were the direct result of withdra-wal of mechanical ventilatory support in weak patientsand, in each case, occurred after unsuccessful weaning

Table 1 Characteristics of non-infected and infectedstudy subjects

Non-infected(n = 16)

Infected(n = 41)

Age (years) 52.4 ± 14.1 55.5 ± 16.7

Gender (%)

Male 44 49

Female 56 51

Body mass index 30.3 ± 9.2 29.8 ± 9.5

Total ICU days 15.1 ± 9.8 34.9 ± 40.2

Days of MV before PdiTwmeasurement

9.1 ± 8.9 10.4 ± 12.4

Steroid usage (%) 50 51

Data presented as mean ± standard deviation. MV, mechanical ventilation;PdiTw, transdiaphragmatic twitch pressure.


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Table 2 Classification of subjects according to presence/absence of active infection at time of PdiTw measurementsa

Subjectnumber

Infected Site Organism(s) isolated from site(s) Diagnosis of infection byattending physician

Antibiotictherapyb

Pulmonaryinfiltrates

1 No No No No

2 Yes Liver abscess Staphylococcus sp., Fusobacteriumnecrophorum

Yes Yes Yes

3 No No No No

4 Yes PAL Streptococcus pneumonia Yes Yes Yes

5 No No No No

6 Yes Blood Gram-positive bacteriac Yes Yes Yes

7 Yes PAL Pseudomonas aeruginosa Yes Yes Yes

8 Yes Blood Staphylococcus species Yes Yes Yes

9 No No No Yesd


11 No No No No

12 Yes Sinuses Bacteroides capillosus, Fusobacteriumsp., b-strep. Gp C

Yes Yes Yes

Nasopharyngealswab

Influenza A

13 No No No No

14 Yes Jejunal drain VRE, Pseudomonas aeruginosa Yes Yes Yes

15 Yes Blood Staphylococcus aureus Yes Yes No

16 No No No No

17 Yes PAL Staphylococcus species Yes Yes Yes

Blood Staphylococcus species

19 Yes PAL Klebsiella pneumonia Yes Yes Yes

20 Yes Blood Staphylococcus aureus Yes Yes No

21 Yes Neck abscess Streptococcus sp. Yes Yes No

22 Yes Sputum Hemophilus parainfluenza Yes Yes Yes

23 Yes Stage IVdecubitus

Pseudomonas aeruginosa, Proteusmirabilis

Yes Yes No

Urine Pseudomonas aeruginosa

24 No No No No

25 No No No No

26 No No No No

27 Yes Subphrenicabscess

Candida glabrata Yes Yes Yes

28 No No No No

29 Yes BAL Escherichia coli, Klebsiella pneumoniae Yes Yes Yes

30 No No No No

31 No No No Yesd

32 Yes Blood Enterococcus faecalis Yes Yes No

33 Yes PAL Staphylococcus aureus Yes Yes Yes

34 Yes Blood Gram-positive coccic Yes Yes Yes

35 Yes ET aspirate Acinetobacter calcoaceticus,Enterobacter cloacae

Yes Yes Yes

Blood Candida

36 Yes PAL Achromobacter xyloxosidans Yes Yes Yes

Central venouscatheter

Pseudomonas aeruginosa


38 Yes Liver abscess Escherichia coli Yes Yes Yes

39 Yes PAL Staphylococcus sp., Enterobacteraerogenes, Escherichia coli

Yes Yes Yes

40 Yes PAL MRSA Yes Yes Yes

Blood MRSA


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Table 2 Classification of subjects according to presence/absence of active infection at time of PdiTw measurementsa

(Continued)

41 Yes Nasopharyngealswab

Influenza B Yes Yes Yes

42 Yes Blood MRSA Yes Yes Yes

Leg abscess MRSA

Osteomyelitis MRSA

44 No No No Yesd

45 No No No No

46 Yes Sputum MRSA Yes Yes Yes

47 Yes PAL Streptococcus pneumonia Yes Yes Yes

49 No No No No

50 Yes Pleural fluid Acinetobacter baumannii, VRE Yes Yes Yes

Pleural tissue Acinetobacter baumannii, VRE

51 Yes Blood Bacillus circulans Yes Yes Yes

52 Yes Blood VRE Yes Yes Yes


Nasopharyngealswab

H1N1

54 Yes Blood VRE Yes Yes Yes

Tracheal aspirate Stenotrophomonas maltophilia

55 Yes PAL MRSA Yes Yes Yes

56 Yes Blood MRSA, Pseudomonas aeruginosa, VRE Yes Yes Yes

Sputum Pseudomonas aeruginosa

57 Yes BAL Samples loste Yes Yes Yes

58 Yes Tracheal aspirate Hemophilus influenza Yes Yes Yes

59 Yes Blood Staphylococcus species Yes Yes No

60 Yes Urine Enterobacter cloacae Yes Yes Yes

PAL Streptococcus sp.aData not included for Subjects 18, 43, and 48 because transdiaphragmatic twitch pressure (PdiTw) measurements were not obtained due to anatomicconstraints. bPatient on antibiotic therapy at the time of PdiTw measurement. cOrganism not speciated - subject treated with antibiotics prior to transfer.dPatientwith pulmonary infiltrates but without evidence of infection (Subject 9 with nonpulmonary acute lung injury, Subject 31 with pulmonary fibrosis, Subject 44 withacute respiratory distress syndrome). eBronchoscopy performed with purulent exudates noted; specimens lost in transit to laboratory. BAL, bronchoalveolarlavage; MRSA, methicillin-resistant Staphylococcus aureus; PAL, protected alveolar lavage; VRE, Enterococcus faecium (vancomycin-resistant).

Table 3 Medication regimen in 57 subjects at the time of transdiaphragmatic twitch pressure measurementsa

Subjectnumber

Antibiotics Other medications Steroid regimen over entire ICU stay

1 Midazolam, metoprolol, hydralazine, calcium acetate,famotidine

2 Piperacillin/tazobactam,vancomycin, levofloxacin,flagyl

Enoxaparin, omeprazole, dobutamine Hydrocortisone 100 mg every 8 hours × 4 days

3 Metoprolol, haloperidol, insulin, aspirin

4 Piperacillin/tazobactam,vancomycin, levofloxacin

Midazolam, fentanyl, pantoprazole

5 Famotidine, trazadone Methylprednisolone 1 g/day × 3 days, prednisone60 mg/day × 2 days, 40 mg/day × 3 days, 30 mg/day ×2 days, 20 mg/day × 2 days, 10 mg/day × 2 days

6 Piperacillin/tazobactam,vancomycin, fluconazole

Midazolam, fentanyl, insulin, lactulose, levothyroxine,norepinephrine, pantoprazole

Hydrocortisone 50 mg every 6 hours × 1 day

7 Piperacillin/tazobactam Midazolam, alprazolam, fentanyl, insulin, famotidine,heparin

8 Vancomycin Midazolam, fentanyl, insulin, famotidine, heparin,simvastatin, gabapentin, venlafaxine, calciumgluconate

Hydrocortisone 50 mg every 8 hours × 8 days


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(Continued)

9 Midazolam, lorazepam, omeprazole, ursodiol,clonidine, levetiracetam, ondansetron,metaclopramide, hydralazine, heparin

10 Piperacillin/tazobactam,vancomycin

Midazolam, famotidine, aspirin, clopidogrel, insulin,heparin, metaclopramide, docusate

Prednisone 20 mg/day × 3 days, Hydrocortisone100 mg every 8 hours × 2 days

11 Midazolam, protonix, amitryptyline, bupropion,carvedilol, clonazepam, folic acid, acetaminophen,digoxin, ondansetron, heparin, tacrolimus

Methylprednisolone 60 mg every 12 hours × 3 days

12 Vancomycin, clindamycin,tamiflu

Midazolam, fentanyl, morphine, heparin, insulin,pantoprazole, bumetanide

Methylprednisolone 60 mg/day × 4 days, prednisone40 mg/day × 3 days

13 Midazolam, enoxaparin, famotidine, insulin,metoprolol, aspirin, hydralazine, lisinopril, simvastatin

14 Vancomycin, levofloxacin,flagyl, aztreonam

Midazolam, fentanyl, heparin Methylprednisolone 60 mg every 12 hours × 6 days

15 Vancomycin Propofol, omeprazole, heparin, amlodipine

16 Midazolam, fentanyl, protonix, ondansetron,darbepoetin, folic acid, cyanocobalamin, hydralazine,amldipine, lisinopril

17 Vancomycin, levofloxacin Midazolam, fentanyl, protonix, insulin, lactulose,levothyroxine, sertraline, hydralazine, gabapentin,carvedilol

19 Vancomycin, piperacillin/tazobactam, levofloxacin

Heparin, hydralazine, labetalol, metoprolol,levetiracetam, lorazepam, omeprazole, phenytoin

Prednisone 20 mg/day × 2 days

20 Vancomycin Midazolam, morphine, amlodipine, labetalol,metoprolol, protonix, phenytoin, heparin

21 Vancomycin, tobramycin,ampicillin/sulbactam

Midazolam, fentanyl, heparin, ibuprofen, amiodarone,metoprolol, omeprazole

22 Vancomycin, levofloxacin Famotidine, heparin, metaclopramide,diphenhydramine

23 Vancomycin, doripenem,colistin

Bumetanide, midazolam, ascorbic acid, famotidine,insulin, vitamin A, zinc, aripiprazole, escitalopram,heparin

24 Paroxetine, pramipexole, simvastatin, omeprazole,heparin, midazolam, insulin, metoprolol, bumetanide

25 Midazolam, heparin, omeprazole, haloperidol,olanzapine, insulin


26 Famotidine, darbepoetin, amlodipine, labetolol, folicacid, thiamine, dexmedetomidine, heparin

27 Doripenem, doxycycline,micafungin, flagyl

Midazolam, fentanyl, promethazine, pantoprazole,levetiracetam, propofol, lactulose

Prednisone 50 mg every 8 hours × 8 days

28 Midazolam, haloperidol, omeprazole, levothyroxine,heparin, insulin, furosemide

29 Doripenem, tobramycin,fluconazole, erythromycin

Morphine, ondansetron, rifaximin, pantoprazole,lactulose, insulin, aspirin, heparin, levetriacetam,midazolam, phenytoin, vasopressin

30 Aspirin, benztropine, famotidine, gabapentin,hydrochlorothiazide, metoclopramide, miralax, insulin,heparin, valproic acid, docusate


31 Azathioprine, bumetanide, clopidogrel, ezetimibe,famotidine, fentanyl, furosemide, heparin, metoprolol,midazolam, nitroglycerin patch, omeprazole,provastatin

Methylprednisilone 125 mg every 6 hours × 3 days,40 mg every 6 hours × 2 days, prednisone60 mg/day × 5 days

32 Vancomycin, gentamycin,aztreonam

Midazolam, fentanyl, aspirin, carbemazepam,haloperidol, metoprolol, omeprazole, phenytoin,insulin, heparin


33 Linezolid Midazolam, lorazepam, fentanyl, aspirin, digoxin,insulin, metoprolol, famotidine, heparin

34 Vancomycin, piperacillin/tazobactam, micofungin

Midazolam, fentanyl, insulin, aspirin, amlodipine,metaclopramide, famotidine, heparin


35 Vancomycin, piperacillin/tazobactam, micofungin,colistin, bactrim

Foscarnate, pantoprazole, diphenhydramine, insulin,fludrocortisone, levothyroxine, ursodiol

Methylprednisolone 10 mg × 1 day


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(Continued)

36 Vancomycin,meraopenum,valgancyclovir, cefipime,dapsone, levofloxacin

Ondansetron, omeprazole, metoprolol,mycophenolate mofetil, sildenafil


37 Piperacillin/tazobactam,vancomycin, levofloxacin

Midazolam, fentanyl, aspirin, heparin, omeprazole,simvastatin

Methylprednisolone 40 mg/day × 2 days, prednisone40 mg/day × 1 day, prednisone 20 mg/day × 3 days

38 Flagyl, levofloxacin,aztreonam

Midazolam, fentanyl, morphine, norepinephrine,vasopressin, famotidine, heparin

39 Doripenam, colistimethate,vancomycin

Midazolam, fentanyl, lortab, zolpidem, metoprolol,omeprazole, heparin

40 Vancomycin, piperacillin/tazobactam, levofloxacin

Midazolam, fentanyl, metaclopramide, aspirin,azathioprine, clopidogrel, furosemide, ondansetron,simvastatin, famotidine, heparin


41 Vancomycin, piperacillin/tazobactam, clindamycin

Midazolam, fentanyl, propofol, insulin, omeprazole

42 Vancomycin, cefipime,levofloxacin, acyclovir

Midazolam, fentanyl, ondansetron, pantoprazole,heparin

44 Midazolam, fentanyl, haloperidol, insulin, famotidine,heparin


45 Midazolam, fentanyl, ondansetron, insulin,omeprazole, heparin


46 Linezolid, piperacillin/tazobactam, tobramycin

Midazolam, Diltiazem, mycophenolate mofetil,tacrolimus, famotidine, insulin, heparin

Hydrocortisone 100 mg every 8 hours × 6 days,prednisone 40 mg/day × 3 days

47 Vancomycin, cefipime,levofloxacin

Midazolam, aspirin, captopril, furosemide, simvastatin,insulin

Prednisone 40 mg/day × 3 days, 30 mg/day × 2 days

49 Midazolam, aspirin, atorvastatin, bisoprolol,clopidogrel, fluticasone, folic acid, pantoprazole,heparin

Methylprednisolone 60 mg every 6 hours × 4 days,40 mg every 12 hours × 2 days, prednisone40 mg/day × 1 day

50 Vancomycin, aztreonam,tobramycin, daptomycin

Midazolam, hydroxyzine, darbepoetin, levothyroxine,ferrous sulfate, ergocalciferol, pancrelipase,omeprazole


51 Vancomycin, piperacillin/tazobactam, doripenam,fluconazaole

Midazolam, fentanyl, furosemide, pancrelipase,magnesium oxide, famotidine, insulin, heparin

52 Vancomycin, piperacillin/tazobactam, daptomycin

Midazolam, fentanyl, levothyroxine, darbepoetin,fluticasone, lactulose, paroxetime, insulin, heparin


53 Tamiflu, piperacillin/tazobactam, cefipime,daptomycin, doripenam

Midazolam, darbepoetin, bumetanide, famotidine,insulin, heparin

54 Vancomycin, piperacillin/tazobactam

Morphine, oxycodone, furosemide, famotidine, insulin,heparin


55 Vancomycin, piperacillin/tazobactam, levofloxacin,daptomycin

Ferrous sulfate, folic acid, levothyroxine,metaclopramide, pravastatin, digoxin tacrolimus,omeprazole, heparin

56 Daptomycin, linezolid,tobramycin, colistin,zithromax

Midazolam, fentanyl, dexmedetomidine, omeprazole,heparin

57 Vancomycin, piperacillin/tazobactam, levofloxacin,tamiflu

Midazolam, fentanyl, clonazepam, gabapentin,famotidine, insulin, heparin

58 Piperacillin/tazobactam Midazolam, morphine, furosemide, metoprolol,citalopram, pantoprazole, aspirin, acetazolamide,insulin, heparin

Methylprednisolone 60 mg every 8 hours × 4 days,prednisone 60 mg/day × 5 days, 40 mg/day ×5 days, 30 mg/day × 5 days

59 Vancomycin, cefipime,levofloxacin

Midazolam, fentanyl, dopamine, norepinephrine,simvastatin, aspirin, omeprazole, heparin

Hydrocortisone 100 mg every 8 hours × 3 days, 50mg every 8 hours × 2 day, 50 mg every 12 hours ×7 days

60 Vancomycin, cefipime,tobramycin

Midazolam, fentanyl, norepinephrine, pantoprazole,heparin

aData not included for Subjects 18, 43, and 48 because transdiaphragmatic twitch pressure measurements not obtained due to anatomic constraint.


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Figure 2 Infection and diaphragm weakness. (A) Transdiaphragmatic twitch pressure (PdiTw) measurements for non-infected and infectedpatients. Data from individual patients are shown for each group on the right, while plots on the left for each group show mean (filled squares),median levels (middle line of box), 25% and 75% confidence intervals (upper and lower borders of the box) and 1% and 99% intervals (whiskersabove and below the box). Infection was associated with significant lower Pdi Twitch values (*statistical significance). (B) respiratory system (RS)static compliance and (C) inspiratory airway resistance for non-infected and infected patients; there was no difference in these indices of lungfunction between non-infected and infected groups.


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Figure 3 Correlation of transdiaphragmatic twitch pressure to blood urea nitrogen, albumin, and glucose levels. Transdiaphragmatictwitch pressure (PdiTw) as a function of (A) blood urea nitrogen (BUN), (B) albumin, and (C) glucose levels. There was no significant correlationbetween any these parameters and PdiTw. Specifically, correlation coefficients and P values for regression of PdiTw to parameters were,respectively, 0.146 and 0.277 for BUN, 0.072 and 0.596 for albumin, and 0.032 and 0.815 for glucose levels (all nonsignificant).


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Figure 4 Relationship of prior duration of mechanical ventilation and ventilator triggering to diaphragm strength .(A) Transdiaphragmatic twitch pressure (PdiTw) as a function of the duration of mechanical ventilation prior to measurement of PdiTw. Therewas no statistically significant correlation of PdiTw to duration of ventilation prior to measurement, with a correlation coefficient of 0.020 andP = 0.881 for this assessment (nonsignificant). (B) The majority of subjects actively initiated (that is, triggered) ventilator breaths more than 75%of the time. (C) The level of diaphragm strength (PdiTw) did not correlate with the level of triggering, with the same PdiTw observed at alltriggering levels.


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Figure 5 Relationship of diaphragm strength to survival. (A) Survival of patients (days after measurement, x axis) as a function oftransdiaphragmatic twitch pressure (PdiTw) level (y axis). Patients that died had low average PdiTw levels (6.3 ± 0.6 cmH2O) while survivors hadhigher PdiTw levels (8.9 ± 0.9 cmH2O, P = 0.044). (B) Survival curves for subjects with PdiTw ≥10 cmH2O (n = 15) and PdiTw <10 cmH2O (n =42). Weak subjects had a significantly higher mortality (49%) than strong subjects (7%, P = 0.022). To exclude the possibility that the greatermortality in the weakest patients may have been due to the presence of more severe lung dysfunction, we also examined (C) respiratory system(RS) static compliance and (D) airway resistance. There was no significant difference in RS static compliance or airway resistance for patients withPdiTw ≥10 cmH2O and PdiTw <10 cmH2O, indicating that the greater mortality ion the weakest patients was not due to concomitant lungdysfunction.


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attempts. Weakness almost certainly contributed to theinability to wean these patients from mechanical ventila-tion and thereby may have influenced the decision towithdraw care.

We also found that a high percentage of patients withPdiTw <10 cmH2O required transfer to LTAC units.Reports indicate that long-term outcomes for this groupof patients are poor, with a high percentage (51%) dying

Figure 6 Relationship of diaphragm strength to ventilator weaning duration. (A) Duration of mechanical ventilation after measurement oftransdiaphragmatic twitch pressure (PdiTw) as a function of the level of PdiTw; each symbol represents data from a single subject. Patients withPdiTw ≥10 cmH2O required significantly shorter times to wean from mechanical ventilation when compared with patients with PdiTw <10cmH2O (P = 0.016). The time required to wean from mechanical ventilation bore no relationship, however, to (B) the respiratory system (RS)static compliance or (C) the airway resistance.


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within 1 year [19]. As a result, the high rate of transfer ofweak patients to these units represents a poor outcome.In addition, we found that the relationship between dia-phragm strength and duration of mechanical ventilationfor patients that did not die and remained in the ICU wascurvilinear, with duration increasing progressively asPdiTw levels fell to lower values (Figure 6A). Weakpatients with PdiTw <10 cmH2O required more thantwice as long to wean from mechanical ventilation thanstronger patients with PdiTw levels ≥10 cmH2O. More-over, the duration of mechanical ventilation did not cor-relate with the level of lung dysfunction but only with thelevel of diaphragm strength.We also evaluated our data to ascertain the role of

infections, BUN, albumin and glucose levels in the induc-tion of diaphragm weakness in mechanically ventilatedpatients. We found the level of diaphragm weakness inmechanically ventilated MICU patients did not correlatewith BUN, glucose, or albumin levels despite previousreports associating these factors with prolonged mechani-cal ventilation [11-13]. In contrast, we found thatevidence of infection was a predictor of strikingly lowerlevels of diaphragm strength than that observed for non-infected patients. This finding is consistent with multipleprevious animal studies demonstrating that infectionrapidly reduces diaphragm force generation, decreasesdiaphragm mitochondrial function, activates diaphragmproteolytic pathways, and reduces diaphragm contractileprotein function [9,20-26].While infected patients had the weakest diaphragms,

even the non-infected mechanically ventilated patients inour study had a median level of PdiTw (13 cmH2O),which is substantially lower than that observed for nor-mal healthy adults (30 cmH2O). There are at least twopotential explanations for the weakness observed in thenon-infected patients. First, many of the patients in ourstudy were chronically ill, with multiple comorbid condi-tions including heart failure, malignancy, liver and renaldiseases. Each of these entities has negative effects onmuscle function, and it is possible that the pre-intubationmuscle function of these patients may have been appreci-ably lower than that observed in normal subjects.In addition, use of mechanical ventilation can result in

diaphragm inactivity and atrophy [27-30]. Numerousanimal studies have provided evidence of this phenom-enon, and, more recently, several elegant studies indicatethat loss of diaphragm function occurs in patients whoare subjected to controlled mechanical ventilation withminimal or no spontaneous respirations [18,27]. Ourpatients were all ventilated using assisted modes ofmechanical ventilation and may therefore have had lessinactivity-induced diaphragm dysfunction than observedin patient populations ventilated with controlled modes

of mechanical ventilation. Nevertheless, it is still possiblethat ventilator-induced inactivity contributed to the levelof diaphragm weakness observed in our non-infectedpatients. As a corollary, the level of weakness observedin our infected patients may represent the combinedeffects of chronic illness, ventilator-induced inactivity,and infection-induced diaphragm dysfunction.One should note, however, that the non-infected

patients had a level of PdiTw (median of 13 cmH2O) thatwas sufficiently high for this group of patients to beexpected to have good outcomes (that is, a low death rateand an average wean time from mechanical ventilation ofabout 5 days) according to the data presented in Figures 5and 6. Only the infected mechanically ventilated patients,as a group, had low enough PdiTw levels (median of 5.5cmH2O) to expect poor outcomes (that is, a high mortalityand a protracted need for mechanical ventilation). Thesedata therefore argue that even if all of the diaphragmweakness observed in our non-infected patients was a con-sequence of ventilator-induced inactivity, this level ofweakness alone would not be expected to result in poorpatient outcomes. Our data would instead suggest thatonly the combination of ventilator-induced inactivity andinfection may produce sufficient diaphragm weakness tonegatively influence patient survival and duration ofmechanical ventilation.

ConclusionsIn summary, we found that mechanically ventilated MICUpatients have severe diaphragm weakness, that the clini-cians caring for these patients greatly underestimate theseverity of diaphragm weakness present, and that infec-tions are a major risk factor for the development of dia-phragm weakness in this population. We also found thatdiaphragm weakness was associated with poor patient out-comes, including a significantly increased mortality, anincreased transfer to LTACs and a markedly longer dura-tion required for weaning from mechanical ventilation.Diaphragm weakness appears to be a major risk factor

for respiratory failure and death in mechanically venti-lated MICU patients; theoretically, pharmacologicaltreatments that improve diaphragm strength shouldreduce the duration of mechanical ventilation andMICU mortality. Currently no such agents are used inclinical practice, but recent experimental studies indicatethat pharmacological inhibition of selected cellular path-ways can prevent diaphragm weakness in animal modelsof critical illness [31,32]. There is an urgent need totranslate these pharmacological treatments from thebench to the bedside in order to prevent or reverse dia-phragm weakness in mechanically ventilated MICUpatients. Such therapies are likely to influence bothacute and long-term outcomes.


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Key messages• Recent work indicates that many mechanically ven-tilated MICU patients have severe diaphragm weak-ness, but the causes and consequences of thisweakness remain controversial.• The present study indicates that infection is amajor risk factor for development of diaphragmweakness in MICU patients treated with assistmodes of mechanical ventilation.• This work also demonstrates that the level of dia-phragm weakness is a novel predictor of clinical out-comes; the weakest patients have a high mortality andrequire prolonged durations of mechanical ventilation.• This study indicates that clinicians underestimatethe severity of diaphragm dysfunction in mechani-cally ventilated critically ill patients.

Additional material

Additional file 1: presents additional methods.

Additional file 2: Table S1 presenting the demographic and clinicaldata in 57 subjects who underwent PdiTw measurements.

Additional file 3: Figure S1. Relationship of PdiTw values to PEEPlevels. PdiTw values are shown as a function of PEEP levels. We foundno correlation between the level of PEEP and PdiTw measurements. Thecorrelation coefficient and p value for regression of PdiTw to PEEP were0.093 and 0.492, respectively (NS).

Additional file 4: Figure S2. Effect of Steroids on PdiTw values.Cumulative dosages of steroids was calculated and converted intohydrocortisone equivalents, then plotted as a function of PdiTw. As shown,steroid dosage had no relationship to measured PdiTw. The correlationcoefficient and p value for regression of PdiTw to hydrocortisoneequivalents were 0.064 and 0.637, respectively (NS).

AbbreviationsBUN: blood urea nitrogen; LTAC: long-term acute care; MICU: medical ICU;PdiTw: transdiaphragmatic twitch pressure; PEEP: positive end-expiratorypressure.

Competing interestsThe authors declare that they have no competing interests.

Authors’ contributionsGSS drafted the protocol, performed the measurements, analyzed thepressure tracings, obtained patient data, interpreted the data, and draftedand revised the final manuscript. LAC assisted in performing themeasurements, obtaining patient data, and had a major impact on theinterpretation of the data and revision of the manuscript. Both authors readand approved the final manuscript.

AcknowledgementsThis work was supported by grants from the National Institutes of Health toGSS (HL 100239 and HL113494).

Received: 23 January 2013 Revised: 9 April 2013Accepted: 20 June 2013 Published: 20 June 2013

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doi:10.1186/cc12792Cite this article as: Supinski and Ann Callahan: Diaphragm weakness inmechanically ventilated critically ill patients. Critical Care 2013 17:R120.

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